Synchronization of vagus nerve stimulation with the cardiac cycle of a patient

ABSTRACT

Disclosed herein are methods, systems, and apparatus for treating a medical condition of a patient, involving detecting a physiological cycle or cycles of the patient and applying an electrical signal to a portion of the patient&#39;s vagus nerve through an electrode at a selected point in the physiological cycle(s). The physiological cycle can be the cardiac and/or respiratory cycle. The selected point can be a point in the cardiac cycle correlated with increased afferent conduction on the vagus nerve, such as a point from about 10 msec to about 800 msec after an R-wave of the patient&#39;s ECG, optionally during inspiration by the patient. The selected point can be a point in the cardiac cycle when said applying increases heart rate variability, such as a point from about 10 msec to about 800 msec after an R-wave of the patient&#39;s ECG, optionally during expiration by the patient.

BACKGROUND OF THE INVENTION

The present application claims priority to and is a continuation of U.S.patent application Ser. No. 14/248,893, filed on Apr. 9, 2014 (Now U.S.Pat. No. 10,835,749), entitled “Synchronization of Vagus NerveStimulation with the Cardiac Cycle of a Patient,” which claims priorityto and is a continuation of U.S. patent application Ser. No. 12/401,026,filed on Mar. 10, 2009 (now U.S. Pat. No. 8,738,126), entitled“Synchronization of Vagus Nerve Stimulation with the Cardiac Cycle of aPatient,” which claims priority to and is a continuation of U.S. patentapplication Ser. No. 11/693,499, filed on Mar. 29, 2007 (now U.S. Pat.No. 8,219,188), entitled “Synchronization of Vagus Nerve Stimulationwith the Cardiac Cycle of a Patient,” which claims priority to U.S.provisional patent application No. 60/787,680, filed on Mar. 29, 2006,all of which are incorporated in their entireties herein by reference.

FIELD OF THE INVENTION

This invention relates generally to medical device systems and, moreparticularly, to medical device systems for applying electrical signalsto a cranial nerve for the treatment of medical conditions, and forimproved electrical signals in such systems.

DESCRIPTION OF THE RELATED ART

Many advancements have been made in treating diseases such as depressionand epilepsy. Therapies using electrical signals for treating thesediseases have been found to effective. Implantable medical devices havebeen effectively used to deliver therapeutic stimulation to variousportions of the human body (e.g., the vagus nerve) for treating thesediseases. As used herein, “stimulation” or “stimulation signal” refersto the application of an electrical, mechanical, magnetic,electro-magnetic, photonic, audio and/or chemical signal to a neuralstructure in the patient's body. The signal is an exogenous signal thatis distinct from the endogenous electrical, mechanical, and chemicalactivity (e.g., afferent and/or efferent electrical action potentials)generated by the patient's body and environment. In other words, thestimulation signal (whether electrical, mechanical, magnetic,electro-magnetic, photonic, audio or chemical in nature) applied to thenerve in the present invention is a signal applied from an artificialsource, e.g., a neurostimulator.

A “therapeutic signal” refers to a stimulation signal delivered to apatient's body with the intent of treating a medical condition byproviding a modulating effect to neural tissue. The effect of astimulation signal on neuronal activity is termed “modulation”; however,for simplicity, the terms “stimulating” and “modulating”, and variantsthereof, are sometimes used interchangeably herein. In general, however,the delivery of an exogenous signal itself refers to “stimulation” ofthe neural structure, while the effects of that signal, if any, on theelectrical activity of the neural structure are properly referred to as“modulation.” The modulating effect of the stimulation signal upon theneural tissue may be excitatory or inhibitory, and may potentiate acuteand/or long-term changes in neuronal activity. For example, the“modulating” effect of the stimulation signal to the neural tissue maycomprise one more of the following effects: (a) initiation of an actionpotential (afferent and/or efferent action potentials); (b) inhibitionor blocking of the conduction of action potentials, whether endogenousor exogenously induced, including hyperpolarizing and/or collisionblocking, (c) affecting changes in neurotransmitter/neuromodulatorrelease or uptake, and (d) changes in neuro-plasticity or neurogenesisof brain tissue.

In some embodiments, electrical neurostimulation may be provided byimplanting an electrical device underneath the skin of a patient anddelivering an electrical signal to a nerve such as a cranial nerve. Inone embodiment, the electrical neurostimulation involves sensing ordetecting a body parameter, with the electrical signal being deliveredin response to the sensed body parameter. This type of stimulation isgenerally referred to as “active,” “feedback,” or “triggered”stimulation. In another embodiment, the system may operate withoutsensing or detecting a body parameter once the patient has beendiagnosed with a medical condition that may be treated byneurostimulation. In this case, the system may apply a series ofelectrical pulses to the nerve (e.g., a cranial nerve such as a vagusnerve) periodically, intermittently, or continuously throughout the day,or over another predetermined time interval. This type of stimulation isgenerally referred to as “passive,” “non-feedback,” or “prophylactic,”stimulation. The electrical signal may be applied by an IMD that isimplanted within the patient's body. In other cases, the signal may begenerated by an external pulse generator outside the patient's body,coupled by an RF or wireless link to an implanted electrode.

Generally, neurostimulation signals that perform neuromodulation aredelivered by the IMD via one or more leads. The leads generallyterminate at their distal ends in one or more electrodes, and theelectrodes, in turn, are electrically coupled to tissue in the patient'sbody. For example, a number of electrodes may be attached to variouspoints of a nerve or other tissue inside a human body for delivery of aneurostimulation signal.

While feedback stimulation schemes have been proposed, conventionalvagus nerve stimulation (VNS) usually involves non-feedback stimulationcharacterized by a number of parameters. Specifically, convention vagusnerve stimulation usually involves a series of electrical pulses inbursts defined by an “on-time” and an “off-time.” During the on-time,electrical pulses of a defined electrical current (e.g., 0.5-2.0milliamps) and pulse width (e.g., 0.25-1.0 milliseconds) are deliveredat a defined frequency (e.g., 20-30 Hz) for the on-time duration,usually a specific number of seconds, e.g., 10-100 seconds. The pulsebursts are separated from one another by the off-time, (e.g., 30seconds-5 minutes) in which no electrical signal is applied to thenerve. The on-time and off-time parameters together define a duty cycle,which is the ratio of the on-time to the combination of the on-time andoff-time, and which describes the percentage of time that the electricalsignal is applied to the nerve.

In conventional VNS, the on-time and off-time may be programmed todefine an intermittent pattern in which a repeating series of electricalpulse bursts are generated and applied to the vagus nerve. Each sequenceof pulses during an on-time may be referred to as a “pulse burst.” Theburst is followed by the off-time period in which no signals are appliedto the nerve. The off-time is provided to allow the nerve to recoverfrom the stimulation of the pulse burst, and to conserve power. If theoff-time is set at zero, the electrical signal in conventional VNS mayprovide continuous stimulation to the vagus nerve. Alternatively, theidle time may be as long as one day or more, in which case the pulsebursts are provided only once per day or at even longer intervals.Typically, however, the ratio of “off-time” to “on-time” may range fromabout 0.5 to about 10.

In addition to the on-time and off-time, the other parameters definingthe electrical signal in conventional VNS may be programmed over a rangeof values. The pulse width for the pulses in a pulse burst ofconventional VNS may be set to a value not greater than about 1 msec,such as about 250-500 μsec, and the number of pulses in a pulse burst istypically set by programming a frequency in a range of about 20-150 Hz(i.e., 20 pulses per second to 150 pulses per second). A non-uniformfrequency may also be used. Frequency may be altered during a pulseburst by either a frequency sweep from a low frequency to a highfrequency, or vice versa. Alternatively, the timing between adjacentindividual signals within a burst may be randomly changed such that twoadjacent signals may be generated at any frequency within a range offrequencies.

Various feedback stimulation schemes have been proposed. In U.S. Pat.No. 5,928,272, the automatic activation of a neurostimulator such as avagus nerve stimulator is described based on a detected increase inheart rate. The '272 patent notes that epilepsy attacks are sometimespreceded by increases in heart rate and proposes automatically applyingan electrical signal to a vagus nerve if the patient's heart rateexceeds a certain level. The patent does not disclose initiating orsynchronizing the therapeutic electrical signal with the patient's heartrhythms. Instead, detection of an abnormal heart rate is used to triggerotherwise conventional VNS.

A new type of stimulation has been proposed known as “microburst”stimulation, which provides enhanced evoked potentials in the brain (asmore fully described in co-pending application Ser. No. 14/089,185,“Microburst Electrical Stimulation Of Cranial Nerves For The TreatmentOf Medical Conditions”). “Enhanced” in this context refers to electricalpotentials evoked in the forebrain by neurostimulation that are higherthan those produced by conventional neurostimulation. The electricalsignal for this improved therapy is substantially different from theelectrical signals in conventional VNS. In particular, electricalsignals in microburst stimulation are characterized by very short burstsof a limited number of electrical pulses. These shorts bursts of lessthan 1 second are referred to hereinafter as “microbursts.” By applyingan electrical signal comprising a series of microbursts to, for example,a vagus nerve of a patient, enhanced vagal evoked potentials (eVEP) areproduced in therapeutically significant areas of the brain.Significantly, eVEP are not produced by conventional vagus nervestimulation.

As used herein, the term “microburst” refers to a portion of atherapeutic electrical signal comprising a limited plurality of pulsesand a limited burst duration. More particularly, a microburst maycomprise at least two but no more than 25 electrical pulses, and maylast for no more than 1 second, and typically less than 100milliseconds, more typically 10-80 msec. A therapeutic electrical signalmay comprise a series of microbursts separated from one another by timeintervals known as “interburst periods” which allow a refractoryinterval for the nervous system to recover from the microburst and againbecome receptive to eVEP stimulation by another microburst. In someembodiments, the interburst period may be as long as or longer than theadjacent microbursts separated by the interburst period. In someembodiments the interburst period may comprise an absolute time periodof at least 100 milliseconds and in some embodiments, up to 6 seconds.Adjacent pulses in a microburst are separated by a time interval knownas an “interpulse interval,” which may comprise a time period from 1msec to 50 msec. The interpulse interval, together with the number ofpulses and the pulse width of each pulse, determines a “microburstduration,” which is the length of a microburst from the beginning of thefirst pulse to the end of the last pulse (and thus the beginning of anew interburst period). Microburst duration in microburst stimulationcan be 1 second or less (i.e., microbursts can be no greater than 1second), and more preferably is 100 msec or less, and still morepreferably is in the range of 10-80 msec. The pulses in a microburst maybe further characterized by a current amplitude and a pulse width.Microburst stimulation may optionally include an on-time and an off-timein which the microbursts are provided and not provided, respectively, toa cranial nerve. At least one of the interburst period, the number ofpulses per burst, the interpulse interval, the microburst duration, thecurrent amplitude, the pulse width, the on-time, or the off-time areselected to enhance cranial nerve evoked potentials.

The timing of neurostimulation signals has heretofore generallyconformed to standard clock cycles, without regard to the efficacy ofneurostimulation signals delivered at particular time-points. Thepresent inventor is unaware of previous investigations of the efficacyof neurostimulation signals delivered at particular time-points ofphysiological cycles.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a method of treating amedical condition of a patient using an implantable medical device,comprising detecting said patient's cardiac cycle and applying anelectrical signal to a portion of a vagus nerve of said patient throughan electrode at a selected point in the cardiac cycle, to treat themedical condition.

In one embodiment, the present invention is a method of treating amedical condition of a patient, comprising: coupling at least oneelectrode to at least one vagus nerve of the patient, providing aprogrammable electrical signal generator coupled to the electrode,detecting said patient's cardiac cycle, generating an electrical signalwith the electrical signal generator, and applying the electrical signalto the electrode to treat the medical condition, and wherein theapplying the electrical signal at a selected point in the cardiac cycle.

Applying an electrical signal at a selected point in a physiologicalcycle may be referred to herein as “synchronizing” the electrical signalwith the physiological cycle. Synchronizing does not requiremodification of one or more electrical signal parameters to match one ormore parameters of the physiological cycle.

In one embodiment, the present invention is a computer readable programstorage device encoded with instructions that, when executed by acomputer, perform a method comprising: detecting said patient's cardiaccycle, generating an electrical signal with the electrical signalgenerator, and applying the electrical signal to an electrode coupled toat least one vagus nerve of the patient to treat the medical condition,and wherein applying the electrical signal to the vagus nerve occurs ata selected point in the cardiac cycle.

In one aspect, the present invention relates to a medical conditiontreatment system comprising at least one electrode coupled to at leastone vagus nerve of a patient, an implantable device operatively coupledto the electrode and comprising an electrical signal generator capableof applying an electrical signal to the vagus nerve at a selected pointin the patient's cardiac cycle, and a device operatively coupled to theelectrode and capable of detecting said patient's cardiac cycle.

In another alternate embodiment, the method may comprise alternatingfirst and second time periods, wherein in the first time period aconventional vagus nerve stimulation electrical signal is applied to avagus nerve of a patient, and a second time period in which microburstelectrical signals are applied to a vagus nerve of a patient. Theconventional vagus nerve stimulation signal may be defined by a currentamplitude, a pulse width, a frequency, an on-time and an off-time. Inone embodiment, the first time period (in which the conventional VNSelectrical signal is applied to the vagus nerve) corresponds to theon-time and the second time period (in which the microburst electricalsignal is applied to the vagus nerve), corresponds to the off-time ofthe conventional vagus nerve signal.

In any embodiment, the selected point in the cardiac cycle can be apoint in the cardiac cycle correlated with increased afferent conductionon the vagus nerve, such as a point from about 10 msec to about 800 msecafter an R-wave of the patient's ECG. In a particular embodiment, theselected point in the cardiac cycle occurs from about 10-800 msec afteran R-wave during inspiration by the patient. In a different embodiment,the selected point in the cardiac cycle occurs from about 10-800 msecafter an R-wave during expiration by the patient. In a furtherembodiment, the selected point in the cardiac cycle occurs from about10-500 msec after an R-wave of the patient's ECG, which may furtheroccur during inspiration, expiration, or without regard to respiration.In another embodiment, the selected point in the cardiac cycle can be apoint in the cardiac cycle when said applying increases heart ratevariability.

In one embodiment, the present invention is a method of treating amedical condition of a patient, comprising: coupling at least oneelectrode to at least one vagus nerve of the patient, providing aprogrammable electrical signal generator coupled to the electrode,detecting said patient's respiratory cycle, generating an electricalsignal with the electrical signal generator, and applying the electricalsignal to the electrode to treat the medical condition, and wherein theapplying the electrical signal at a selected point in the respiratorycycle.

In a further embodiment, the present invention is a method of treating amedical condition of a patient, comprising: coupling at least oneelectrode to at least one vagus nerve of the patient, providing aprogrammable electrical signal generator coupled to the electrode,detecting said patient's respiratory cycle and cardiac cycle, generatingan electrical signal with the electrical signal generator, and applyingthe electrical signal to the electrode to treat the medical condition,and wherein the applying the electrical signal at a selected point inthe respiratory cycle and/or cardiac cycle.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be understood by reference to the followingdescription taken in conjunction with the accompanying drawings, inwhich like reference numerals identify like elements, and in which:

FIG. 1 provides a stylized diagram of an implantable medical deviceimplanted into a patient's body for providing a therapeutic electricalsignal to a neural structure of the patient's body, in accordance withone illustrative embodiment of the present invention;

FIG. 2A is a block diagram of a medical device system that includes animplantable medical device and an external device for providing apatient management system for the implantable medical device, inaccordance with one illustrative embodiment of the present invention;

FIG. 3 illustrates an exemplary electrical signal of a firing neuron asa graph of voltage at a given location at particular times in responseto application of an electrical signal to the nerve by theneurostimulator of FIG. 2 , in accordance with one illustrativeembodiment of the present invention;

FIGS. 4A, 4B, and 4C illustrate exemplary waveforms for generating theelectrical signals for stimulating the vagus nerve for treating amedical condition, according to one illustrative embodiment of thepresent invention;

FIG. 5 illustrates a flowchart depiction of a method for treating amedical condition, in accordance with an illustrative embodiment of thepresent invention;

FIG. 6 illustrates a flowchart depiction of an alternative method fortreating a medical condition, in accordance with an alternativeillustrative embodiment of the present invention;

FIG. 7 depicts a more detailed flowchart depiction of the step ofperforming a detection process of FIG. 6 , in accordance with anillustrative embodiment of the present invention; and

FIG. 8 illustrates synchronization of a vagal stimulus burst to the QRSwave of a patient's ECG.

FIG. 9 illustrates a second pulsed electrical signal that is not amicroburst signal.

While the invention is susceptible to various modifications andalternative forms, specific embodiments thereof have been shown by wayof example in the drawings and are herein described in detail. It shouldbe understood, however, that the description herein of specificembodiments is not intended to limit the invention to the particularforms disclosed, but on the contrary, the intention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the invention as defined by the appended claims.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

Illustrative embodiments of the invention are described herein. In theinterest of clarity, not all features of an actual implementation aredescribed in this specification. In the development of any such actualembodiment, numerous implementation-specific decisions must be made toachieve the design-specific goals, which will vary from oneimplementation to another. It will be appreciated that such adevelopment effort, while possibly complex and time-consuming, wouldnevertheless be a routine undertaking for persons of ordinary skill inthe art having the benefit of this disclosure.

This document does not intend to distinguish between components thatdiffer in name but not function. In the following discussion and in theclaims, the terms “including” and “includes” are used in an open-endedfashion, and thus should be interpreted to mean “including, but notlimited to.” Also, the term “couple” or “couples” is intended to meaneither a direct or an indirect electrical connection. “Direct contact,”“direct attachment,” or providing a “direct coupling” indicates that asurface of a first element contacts the surface of a second element withno substantial attenuating medium there between. The presence of smallquantities of substances, such as bodily fluids, that do notsubstantially attenuate electrical connections does not vitiate directcontact. The word “or” is used in the inclusive sense (i.e., “and/or”)unless a specific use to the contrary is explicitly stated.

The term “electrode” or “electrodes” described herein may refer to oneor more stimulation electrodes (i.e., electrodes for delivering anelectrical signal generated by an IMD to a tissue), sensing electrodes(i.e., electrodes for sensing a physiological indication of a patient'sbody), and/or electrodes that are capable of delivering a stimulationsignal, as well as performing a sensing function.

Cranial nerve stimulation has been proposed to treat a number of medicalconditions pertaining to or mediated by one or more structures of thenervous system of the body, including epilepsy and other movementdisorders, depression, anxiety disorders and other neuropsychiatricdisorders, dementia, head trauma, coma, migraine headache, obesity,eating disorders, sleep disorders, cardiac disorders (such as congestiveheart failure and atrial fibrillation), hypertension, endocrinedisorders (such as diabetes and hypoglycemia), and pain, among others.See, e.g., U.S. Pat. Nos. 4,867,164; 5,299,569; 5,269,303; 5,571,150;5,215,086; 5,188,104; 5,263,480; 6,587,719; 6,609,025; 5,335,657;6,622,041; 5,916,239; 5,707,400; 5,231,988; and 5,330,515. Despite thenumerous medical conditions for which cranial nerve stimulation has beenproposed or suggested as a treatment option, the fact that detailedneural pathways for many (if not all) cranial nerves remain relativelyunknown, makes predictions of efficacy for any given medical conditiondifficult or impossible. Moreover, even if such pathways were known, theprecise stimulation parameters that would modulate particular pathwaysrelevant to a particular medical condition generally cannot bepredicted.

In one embodiment, the present invention relates to a method of treatinga medical condition selected from the group consisting of epilepsy,neuropsychiatric disorders (including but not limited to depression),eating disorders/obesity, traumatic brain injury/coma, addictiondisorders, dementia, sleep disorders, pain, migraine,endocrine/pancreatic disorders (including but not limited to diabetes),motility disorders, hypertension, congestive heart failure/cardiaccapillary growth, hearing disorders, angina, syncope, vocal corddisorders, thyroid disorders, pulmonary disorders, and reproductiveendocrine disorders (including fertility) in a patient.

The present invention relates to synchronization of cranial nerveelectrical stimulation to a physiological event, such as a specificpoint in the cardiac cycle and/or respiratory cycle. Synchronization ofsuch electrical stimulation signals may, in one embodiment, be performedby an implantable medical device (IMD) system. An IMD system maycomprise an implantable medical device for delivering a therapeuticelectrical signal and sensing/recording data, and an external device(ED) capable of programming and/or data transfer operations with theIMD.

The medical device system of the present invention provides for softwaremodule(s) that are capable of acquiring, storing, and processing one ormore forms of data, such as patient data/parameters (e.g., physiologicaldata such as heart rate, cardiac cycle data and respiration cycle data,side-effects data, brain-activity data, disease progression orregression data, self-evaluation data, seizure characteristic data,quality of life data, etc.) and therapy parameter data. Therapyparameters may include, but are not limited to, electrical signalparameters that define the therapeutic electrical signals delivered bythe medical device, medication parameters (e.g., dosages, frequency ofmedication provided to the patient, etc.) and/or any other therapeutictreatment parameter. In an alternative embodiment, the term “therapyparameters” may refer to electrical signal parameters defining thetherapeutic electrical signals delivered by the medical device. Therapyparameters for a therapeutic electrical signal may also include, but arenot limited to, an interburst period, a number of pulses per burst, aninterpulse interval, a burst duration, a current amplitude, a pulsewidth, a pulse frequency, a signal on-time, a signal off-time, and/or aduty cycle.

Although not so limited, a system capable of implementing embodiments ofthe present invention is described below. FIG. 1 depicts a stylizedimplantable medical device (IMD) 100 for implementing one or moreembodiments of the present invention. An electrical signal generator 110is provided, having a main body 112 comprising a case or shell with aheader 116 for connecting to an insulated, electrically conductive leadassembly 122. The generator 110 is implanted in the patient's chest in apocket or cavity formed by the implanting surgeon just below the skin(indicated by a dotted line 145), similar to the implantation procedurefor a pacemaker pulse generator.

A nerve electrode assembly 125, preferably comprising a plurality ofelectrodes having at least an electrode pair, is conductively connectedto the distal end of the lead assembly 122, which preferably comprises aplurality of lead wires (one wire for each electrode). Each electrode inthe electrode assembly 125 may operate independently or alternatively,may operate in conjunction with the other electrodes. In one embodiment,the electrode assembly 125 comprises at least a cathode and an anode. Inanother embodiment, the electrode assembly comprises one or moreunipolar electrodes.

Lead assembly 122 is attached at its proximal end to connectors on theheader 116 of generator 110. The electrode assembly 125 may besurgically coupled to a vagus nerve 127 in the patient's neck or atanother location, e.g., near the patient's diaphragm or at theesophagus/stomach junction. Other (or additional) cranial nerves such asthe trigeminal and/or glossopharyngeal nerves may also be used todeliver the electrical signal in particular alternative embodiments. Inone embodiment, the electrode assembly 125 comprises a bipolarstimulating electrode pair 126, 128 (i.e., a cathode and an anode).Suitable electrode assemblies are available from Cyberonics, Inc.,Houston, Tex., USA as the Model 302 electrode assembly. However, personsof skill in the art will appreciate that many electrode designs could beused in the present invention. In one embodiment, the two electrodes arewrapped about the vagus nerve 127, and the electrode assembly 125 may besecured to the vagus nerve 127 by a spiral anchoring tether 130 such asthat disclosed in U.S. Pat. No. 4,979,511 issued Dec. 25, 1990 to ReeseS. Terry, Jr. and assigned to the same assignee as the instantapplication. Lead assembly 122 may be secured, while retaining theability to flex with movement of the chest and neck, by a sutureconnection to nearby tissue (not shown).

In some embodiments, the electrode assembly 125 may comprise temperaturesensing elements, heart rate or cardiac cycle sensor elements, and/orrespiration cycle sensing elements. In one embodiment, the electrodeassembly 125 comprises a strain gauge that may be used to determineinspiration by identifying chest expansion. By detecting the onset ofchest expansion, the strain gauge may detect the onset of inspiration.The strain gauge may also detect expiration by identifying when thechest is contracting. Other sensors for other body parameters may alsobe employed to trigger active stimulation. Both passive and activestimulation may be combined or delivered by a single IMD according tothe present invention. Either or both modes may be appropriate to treata specific patient under observation.

In one embodiment, a sensor assembly 165, comprising a sensor leadassembly 162 and a sensor 160, may be employed to detect a bodyparameter of the patient, such as a parameter related to the patient'scardiac cycle. The sensor 160 may be one or more electrocardiogram leadsor a heart rate monitor, among other sensing devices.

The electrical pulse generator 110 may be programmed with an externaldevice (ED) such as computer 150 using programming software known in theart. A programming wand 155 may be coupled to the computer 150 as partof the ED to facilitate radio frequency (RF) communication between thecomputer 150 and the pulse generator 110. The programming wand 155 andcomputer 150 permit non-invasive communication with the generator 110after the latter is implanted. In systems where the computer 150 usesone or more channels in the Medical Implant Communications Service(MICS) bandwidths, the programming wand 155 may be omitted to permitmore convenient communication directly between the computer 150 and thepulse generator 110.

The IMD 100 may detect one or more portions of patient's cardiac cycle,e.g., P waves, R waves, R-R interval, QRS complex, T waves, etc., or theentire PQRST cycle. In response to detecting the one or more portions ofthe cardiac cycle, the IMD 100 may cause the pulse generator 110 todeliver an electrical signal via leads 122 to a cranial nerve such asvagus nerve 127 at a particular point during the cardiac cycle. Forexample, a sensor 160, such as a heart rate monitor or a set ofelectrocardiogram (ECG) leads, may be used to detect the one or moreportions of the patient's cardiac cycle. The detected portion of thecardiac cycle may then be used to trigger the pulse generator 110 togenerate the therapeutic electrical signal and apply the signal to thevagus nerve 127.

A “cardiac cycle” herein refers to the electrical activity of apatient's heart that occurs in the period between the onset ofconsecutive P waves. This electrical activity may be measured andanalyzed by an electrocardiogram (ECG). The cycle begins with the Pwave, which corresponds to electrical depolarization of the atria of theheart. As is known, an electrocardiogram exhibits a P wave, a QRScomplex, and a T wave, and in some patients it may also exhibit a Uwave. An isoelectric baseline follows from the end of the T or U wave tothe onset of the next P wave with the patient's next heartbeat.

According to one aspect of the present invention, conventional burstsand/or microbursts of electrical pulses comprising an electrical signalare applied to the vagus nerve in synchronization with one or moreportions of the cardiac cycle. In one embodiment, the electrical signalis synchronized with the R wave of a patient's cardiac cycle. In anotherembodiment, the signal is synchronized with the QRS complex. In afurther embodiment, the signal is further synchronized with therespiration cycle of the patient. In a still further embodiment, thetherapeutic electrical signal is synchronized with both a portion of thepatient's cardiac cycle and the respiration cycle of the patient.Synchronization of the application of the therapeutic electrical signalwith the patient's cardiac and/or respiration cycles enables the IMD toaugment endogenous cardiac-related and/or respiration-related vagalafferent activity with the exogenous electrical signal. In oneembodiment, as illustrated in FIG. 8 , the neurostimulation burst istriggered by the R-wave of the ECG after a delay period, which comprisesa predetermined or random time interval that may range, e.g., from˜10-800 msec following detection of the R-wave. In another embodiment,the therapeutic electrical signal is applied to the vagus nerve after apredetermined or random time interval, e.g. ˜10-1000 msec following thebeginning of inspiration by the patient. In one further embodiment, theIMD 100 applies an electrical signal to a cranial nerve, such as vagusnerve 127, beginning at a point from about 10 msec to about 800 msecafter an R-wave of the patient's ECG when the patient is inspiring.Without being bound by theory, it is believed that synchronizing theapplication of the exogenous therapeutic electrical signal to the vagusnerve with the detection of the R-wave of the patient's cardiac cycleand/or the beginning of inspiration by the patient may increase theefficacy of neurostimulation therapy by entraining the exogenous signalwith the endogenous cyclic facilitation of central vagal afferentpathways.

In one embodiment, a first electrical signal is applied in synchronywith the patient's cardiac and/or respiratory cycles, as describedabove, and a second electrical signal is applied without reference tothe patient's physiological cycle, wherein the second electrical signaldiffers from the first in at least one parameter selected from the groupconsisting of a burst duration, a number of pulses per burst, aninterpulse interval, an interburst period, a current magnitude, a pulsefrequency, a signal width, an on-time, and an off-time.

In another embodiment, the synchronization of the exogenous electricalsignal further comprises not providing the exogenous signal duringperiods in the opposite half of the cardiac and/or respiratory dutycycles, when the central pathways are inhibited. Again without beingbound by theory, it is believed that asynchronously-appliedneurostimulation signals in other portions of the cardiac and/orrespiratory cycles may be less effective because endogenous signals inthose portions of the cardiac and/or respiratory cycles are lesssignificant, in terms of their information content, for modulating thoseportions of the brain relevant to homeostasis mechanisms implicated inmedical conditions such as epilepsy and depression, among others. Thus,at least a portion of the exogenous electrical signal in conventionalstimulation algorithms may be therapeutically irrelevant, or evencounterproductive.

Accordingly, in one embodiment, the therapeutic electrical signal burstor microburst is applied to the cranial nerve, such as the vagus nerve127, after a delay period of, e.g., ˜10-800 msec following detection ofthe R-wave, and no signal is applied during the remaining portions ofone or more subsequent cardiac cycles. In another embodiment, thetherapeutic electrical signal is applied to the vagus nerve after adelay period of ˜10-1000 msec following the beginning of inspiration bythe patient, and no signal is applied to the nerve during the remainingportions of the respiration cycle. In still another embodiment, thetherapeutic electrical signal is applied to the vagus nerve after adelay period following detection of the R-wave only if the patient isinspiring, and otherwise no signal is applied to the vagus nerve.

A patient's heart rate can vary due to a number of reasons, includingvariations in activity level (e.g., exercise or other exertion),variations in emotional state, or variations in breathing, among others.In generally healthy patients, heart rate variability (HRV) of about0.15 Hz to about 0.4 Hz is observed with respiration (breathing), withheart rate increasing during inspiration (inhalation) and decreasingduring expiration (exhaling). HRV can decrease or increase greatlyduring meditation, and can increase by the practice of slow, pacedbreathing. Observers have noted a correlation betweenrespiration-related HRV of about 0.15 Hz to about 0.4 Hz and physicalhealth, including greater immune function, lower incidence of cardiacarrhythmia, and a greater prevalence of commonly-preferred emotionalstates (e.g., more “happiness” and less “sadness”) relative to personshaving respiration-related HRV below 0.15 Hz. Consequently, it may bebeneficial for the patient to begin paced breathing during the pulseburst. Further, it may improve the efficacy of the exogenous electricalsignal if the pulses are triggered while the patient is performing pacedbreathing. The beneficial effects of the paced breathing coupled withthe therapeutic effects of the microbursts may increase the efficacy ofthe stimulation. Respiration-related HRV can be determined by monitoringheart rate or electrocardiography and calculating intervals betweenheart beats or particular points in consecutive cardiac cycles, such asconsecutive R-waves. The variations in HRV can be used to indicateperiods when the R-R interval is decreasing (corresponding toinspiration as the heart rate accelerates, thus reducing the duration ofR-R interval relative to the prior R-R interval) or increasing(corresponding to expiration as the heart rate decelerates, thusincreasing the R-R interval duration relative to the prior R-Rinterval). Alternatively, the IMD system 100 may detect the highfrequency (0.18-0.4 Hz) component of the HRV power spectrum to determinewhen inspiration occurs. It will be appreciated that differenttechniques to detect cardiac cycles and respiration may be used,including separate sensors for heart rate and breathing, and that allsuch techniques are within the scope of the present invention.

In one embodiment, the IMD 100 applies a therapeutic electrical signalto the cranial nerve, such as the vagus nerve 127, at a point in thecardiac cycle correlated with increased afferent conduction on thecranial nerve, such as the vagus nerve 127. This may be done by sensingelectrical activity on the vagus nerve and initiating the therapeuticelectrical signal when the electrical activity increases. Without beingbound by theory, since it is believed that increased electrical activitycorresponds with inspiration and/or appropriate portions of the cardiaccycle, such a technique could result in supplementing the endogenouscentral vagal activity relevant to the patient's medical condition withthe therapeutic, exogenous electrical signal.

In one embodiment, the IMD 100 applies an electrical signal to thecranial nerve, such as the vagus nerve 127, at a point in the cardiaccycle when applying the signal increases heart rate variability. In onefurther embodiment, the IMD 100 applies an electrical signal to thecranial nerve, such as the vagus nerve 127, beginning at a point fromabout 10 msec to about 800 msec after an R-wave of the patient's ECGduring expiration (exhalation) by the patient.

In one embodiment, the IMD 100 does not apply an electrical signal tothe cranial nerve, such as the vagus nerve 127, at a point during thecardiac cycle correlated with increased efferent conduction on thecranial nerve.

In one embodiment, stimulation may be applied to generate efferentelectrical activity on the nerve, which refers to signals traveling on anerve in a direction away from the central nervous system. In anotherembodiment, a “blocking” type of electrical signal may be employed usingthe IMD 100, such that both afferent and efferent electrical activity onthe nerve is prevented from traveling further. Thus, the IMD 100 mayoperate to “silence” the vagus nerve.

Further, or alternatively, afferent stimulation may also be performed,wherein afferent fibers are stimulated while efferent fibers are notstimulated or are blocked. Afferent stimulation may be especially potentat times when the nerve conducts a relatively large number of afferentsignals. For the vagus nerve, an example of such a time is about 10 msecto about 800 msec after the R-wave of the cardiac cycle.

In addition to electrical signals to generate efferent or afferentelectrical activity on the nerve, the blocking type of stimulationdescribed above may also be applied to the nerve. Efferent blocking maybe realized by enhancing the hyper polarization of a stimulation signal,as described below. Embodiments of the present invention may employ theIMD 100 to perform afferent or efferent stimulation in combination withsignal blocking, in order to treat medical conditions. Using thestimulation from the IMD 100, cranial nerve portions may be inhibitedsuch that blocking of action potentials is achieved, wherein the variousportions of the cranial nerve may also be stimulated to affect amechanism in the patients' body.

The electrical stimulation treatment described herein may be used totreat a medical condition separately, or in combination with anothertype of treatment. For example, electrical stimulation treatment may beapplied in combination with a chemical agent, such as various drugs, totreat various medical conditions. Therefore, various drugs may be takenby a patient, wherein the effects of these drugs may be enhanced byproviding electrical stimulation to various portions of the nervesdescribed herein to treat medical conditions. Further, the electricalstimulation may be performed in combination with treatment(s) relatingto a biological or chemical agent. Therefore, drug therapy may beenhanced by the application of the stimulation provided by the IMD 100.The electrical stimulation treatment may also be performed incombination with other types of treatment, such as transcranial magneticstimulation (TMS) treatment. Combining the electrical stimulation withthe chemical, magnetic, or biological treatments, side effectsassociated with certain drugs or biological agents may be reduced.

Turning now to FIG. 2 , a block diagram depiction of the IMD 200 isprovided, in accordance with one illustrative embodiment of the presentinvention. The IMD 200 (such as generator 110 from FIG. 1 ) may comprisea controller 210 capable of controlling various aspects of the operationof the IMD 200. The controller 210 is capable of receiving internal dataor external data and causing a stimulation unit 220 to generate anddeliver an electrical signal to target tissues of the patient's body fortreating a medical condition. For example, the controller 210 mayreceive manual instructions from an operator externally, or may causethe electrical signal to be generated and delivered based on internalcalculations and programming. The controller 210 is capable of affectingsubstantially all functions of the IMD 200.

The controller 210 may comprise various components, such as a processor215, a memory 217, etc. The processor 215 may comprise one or moremicrocontrollers, microprocessors, etc., capable of performing variousexecutions of software components. The memory 217 may comprise variousmemory portions where a number of types of data (e.g., internal data,external data instructions, software codes, status data, diagnosticdata, etc.) may be stored. The memory 217 may comprise one or more ofrandom access memory (RAM) dynamic random access memory (DRAM),electrically erasable programmable read-only memory (EEPROM), flashmemory, etc.

The IMD 200 may also comprise a stimulation unit 220 capable ofgenerating and delivering electrical signals to one or more electrodesvia leads. A lead assembly such as lead assembly 122 (FIG. 1 ) may becoupled to the IMD 200. Therapy may be delivered to the leads comprisingthe lead assembly 122 by the stimulation unit 220 based uponinstructions from the controller 210. The stimulation unit 220 maycomprise various circuitry, such as electrical signal generators,impedance control circuitry to control the impedance “seen” by theleads, and other circuitry that receives instructions relating to thedelivery of the electrical signal to tissue. The stimulation unit 220 iscapable of delivering an electrical signal over the leads comprising thelead assembly 122.

The IMD 200 may also comprise a power supply 230. The power supply 230may comprise a battery, voltage regulators, capacitors, etc., to providepower for the operation of the IMD 200, including delivering thetherapeutic electrical signal. The power supply 230 comprises a powersource that in some embodiments may be rechargeable. In otherembodiments, a non-rechargeable power source may be used. The powersupply 230 provides power for the operation of the IMD 200, includingelectronic operations and the electrical signal generation and deliveryfunctions. The power supply 230 may comprise a lithium/thionyl chloridecell or a lithium/carbon monofluoride (LiCFx) cell. Other battery typesknown in the art of implantable medical devices may also be used.

The IMD 200 may also comprise a communication unit 260 capable offacilitating communications between the IMD 200 and various devices. Inparticular, the communication unit 260 is capable of providingtransmission and reception of electronic signals to and from an externalunit 270, such as computer 150 and wand 155 that may comprise an ED(FIG. 1 ). The communication unit 260 may include hardware, software,firmware, or any combination thereof.

The IMD 200 also comprises a detection unit 295 that is capable ofdetecting various patient parameters. For example, the detection unit295 may comprise hardware, software, or firmware that is capable ofobtaining and/or analyzing data relating to one or more body parametersof the patient, such as heart rate, cardiac cycle data, and/orrespiratory cycle data. Based upon the data obtained by the detectionunit 295, the IMD 200 may deliver the electrical signal to a portion ofthe vagus nerve to treat epilepsy, depression or other medicalconditions. In one embodiment, the detection unit 295 may be capable ofdetecting a feedback response from the patient. The feedback responsemay include a magnetic signal input, a tap input, a wireless data inputto the IMD 200, etc. The feedback may be indicative of a pain and/ornoxious threshold, wherein the threshold may be the limit of toleranceof discomfort for a particular patient. The term “patient parameters”may refer to, but is not limited to, various body parameters, which mayin some embodiments involve sensors coupled to the IMD 200.

In another embodiment, the detection unit 295 may comprise hardware,software, or firmware that is capable of obtaining and/or analyzing datarelating to one or more body parameters of the patient's cardiac cycle.Based upon the data obtained by the detection unit 295, the IMD 200 maydeliver the electrical signal to a portion of the vagus nerve at one ormore particular points in the cardiac cycle to treat epilepsy,depression or other medical conditions.

The external unit 270 may be an ED that is capable of programmingelectrical signal parameters of the IMD 200. In one embodiment, theexternal unit 270 is a computer system capable of executing adata-acquisition program. The external unit 270 may be controlled by ahealthcare provider, such as a physician, at a base station in, forexample, a doctor's office. In alternative embodiments, the externalunit 270 may be controlled by a patient in a system providing lesscontrol over the operation of the IMD 200 than another external unit 270controlled by a healthcare provider. Whether controlled by the patientor by a healthcare provider, the external unit 270 may be a computer,preferably a handheld computer or PDA, but may alternatively compriseany other device that is capable of electronic communications andprogramming, e.g., hand-held computer system, a PC computer system, alaptop computer system, a server, a personal digital assistant (PDA), anApple-based computer system, etc. The external unit 270 may downloadvarious parameters and program software into the IMD 200 for programmingthe operation of the IMD, and may also receive and upload various statusconditions and other data from the IMD 200. Communications between theexternal unit 270 and the communication unit 260 in the IMD 200 mayoccur via a wireless or other type of communication, representedgenerally by line 277 in FIGS. 2A and 2B. This may occur using, e.g.,wand 155 (FIG. 1 ) to communicate by RF energy with a generator 110.Alternatively, the wand may be omitted in some systems, e.g., systems inwhich external unit 270 operates in the MICS bandwidths.

In one embodiment, the external unit 270 may comprise a local databaseunit 255. Optionally or alternatively, the external unit 270 may also becoupled to a database unit 250, which may be separate from external unit270 (e.g., a centralized database wirelessly linked to a handheldexternal unit 270). The database unit 250 and/or the local database unit255 are capable of storing various patient data. This data may comprisepatient parameter data acquired from a patient's body and/or therapyparameter data. The database unit 250 and/or the local database unit 255may comprise data for a plurality of patients, and may be organized andstored in a variety of manners, such as in date format, severity ofdisease format, etc. The database unit 250 and/or the local databaseunit 255 may be relational databases in one embodiment. A physician mayperform various patient management functions using the external unit270, which may include obtaining and/or analyzing data from the IMD 200and/or data from the database unit 250 and/or the local database unit255. The database unit 250 and/or the local database unit 255 may storevarious patient data such as heart rate data, cardiac cycle data (suchas R-R interval data), respiratory cycle information, etc.

One or more of the blocks illustrated in the block diagram of the IMD200 in FIG. 2 , may comprise hardware units, software units, firmwareunits, or any combination thereof. Additionally, one or more blocksillustrated in FIG. 2 may be combined with other blocks, which mayrepresent circuit hardware units, software algorithms, etc.Additionally, any number of the circuitry or software units associatedwith the various blocks illustrated in FIG. 2 may be combined into aprogrammable device, such as a field programmable gate array, an ASICdevice, etc.

FIG. 3 provides a stylized depiction of an exemplary electrical signalof a firing neuron as a graph of voltage at a given point on the nerveat particular times during the propagation of an action potential alongthe nerve, in accordance with one embodiment of the present invention. Atypical neuron has a resting membrane potential of about −70 mV,maintained by transmembrane ion channel proteins. When a portion of theneuron reaches a firing threshold of about −55 mV, the ion channelproteins in the locality allow the rapid ingress of extracellular sodiumions, which depolarizes the membrane to about +30 mV. The wave ofdepolarization then propagates along the neuron. After depolarization ata given location, potassium ion channels open to allow intracellularpotassium ions to exit the cell, lowering the membrane potential toabout −80 mV (hyperpolarization). About 1 msec is required fortransmembrane proteins to return sodium and potassium ions to theirstarting intra- and extracellular concentrations and allow a subsequentaction potential to occur.

Referring again to FIG. 1 , the IMD 100 may generate a pulsed electricalsignal in embodiments of the present invention for application to acranial nerve such as vagus nerve 127 according to one or moreprogrammed parameters. In one embodiment, the electrical signal may be aconventional vagus nerve therapeutic electrical signal defined by aplurality of parameters such as current magnitude, pulse width,frequency, on-time and off-time. In another embodiment, the electricalsignal may be a microburst signal defined by a plurality of parameterssuch as an interburst period, a number of a number of pulses per burst,an interpulse interval, a burst duration, a current magnitude, a pulsewidth, an on-time, and an off-time. In yet another embodimentillustrated in FIG. 9 , the electrical signal may comprise a first timeperiod in which conventional vagus nerve therapeutic electrical signals1000 are applied to the nerve, and a second time period in whichmicroburst electrical signals are applied to the nerve. In a stillfurther embodiment, conventional and microburst signals are alternatedwith a defined off-time in a conventional on-time and a microburston-time. Thus a 30 second burst of a conventional VNS signal may befollowed by 5 minutes off-time, followed by a 1 minute period ofmicroburst stimulation, followed by a 5 minute off-time, after which theprocess repeats itself.

Exemplary pulse waveforms in accordance with one embodiment of thepresent invention are shown in FIGS. 4A-4C. Pulse shapes in electricalsignals according to the present invention may include a variety ofshapes known in the art including square waves, biphasic pulses(including active and passive charge-balanced biphasic pulses),triphasic waveforms, etc. In one embodiment, the pulses comprise asquare, biphasic waveform in which the second phase is acharge-balancing phase of the opposite polarity to the first phase.

In addition to conventional programmed or random off-time periods (andwhether conventional or microburst stimulation is applied), the durationof a period of “off-time” in embodiments of the present invention may bevaried with changes in the patient's cardiac cycle. In one embodiment,the “off-time” begins about 10 msec to about 800 msec after the onset ofthe R-wave of a patient's cardiac cycle and ends at the onset of theR-wave of a later cardiac cycle of the patient, such as the next cardiaccycle.

In one embodiment, the present invention may include coupling of atleast one electrode to each of two or more cranial nerves. (In thiscontext, two or more cranial nerves mean two or more nerves havingdifferent names or numerical designations, and do not refer to the leftand right versions of a particular nerve). In one embodiment, at leastone electrode may be coupled to each of the vagus nerves 127 or a branchof either vagus nerve. The term “operatively” coupled may includedirectly or indirectly coupling. Each of the nerves in this embodimentor others involving two or more cranial nerves may be stimulatedaccording to particular activation modalities that may be independentbetween the two nerves.

Another activation modality for stimulation is to program the output ofthe IMD 100 to the maximum amplitude which the patient may tolerate. Thestimulation may be cycled on and off for a predetermined period of timefollowed by a relatively long interval without stimulation. Where thecranial nerve stimulation system is completely external to the patient'sbody, higher current amplitudes may be needed to overcome theattenuation resulting from the absence of direct contact with thecranial nerve and the additional impedance of the skin of the patient.Although external systems typically require greater power consumptionthan implantable ones, they have an advantage in that their batteriesmay be replaced without surgery.

Returning to systems for providing cranial nerve stimulation, such asthat shown in FIGS. 1 and 2 , stimulation may be provided in eithernon-feedback or feedback modalities. Where cranial nerve stimulation isprovided based solely on programmed off-times and on-times, thestimulation may be referred to as passive, inactive, or non-feedbackstimulation. In contrast, stimulation may be triggered by one or morefeedback loops according to changes in the body or mind of the patient.This stimulation may be referred to as active or feedback-loopstimulation. In one embodiment, feedback-loop stimulation may bemanually-triggered stimulation, in which the patient manually causes theactivation of a pulse burst outside of the programmed on-time/off-timecycle. The patient may manually activate the IMD 100 to stimulate thevagus nerve 127 to treat an acute episode of a medical condition. Thepatient may also be permitted to alter the intensity of the signalsapplied to the cranial nerve within limits established by the physician.

Patient activation of an IMD 100 may involve use of an external controlmagnet for operating a reed switch in an implanted device, for example.Certain other techniques of manual and automatic activation ofimplantable medical devices are disclosed in U.S. Pat. No. 5,304,206 toBaker, Jr., et al., assigned to the same assignee as the presentapplication (“the '206 patent”). According to the '206 patent, means formanually activating or deactivating the electrical signal generator 110may include a sensor such as piezoelectric element mounted to the innersurface of the generator case and adapted to detect light taps by thepatient on the implant site. One or more taps applied in fast sequenceto the skin above the location of the electrical signal generator 110 inthe patient's body may be programmed into the implanted medical device100 as a signal for activation of the electrical signal generator 110.Two taps spaced apart by a slightly longer duration of time may beprogrammed into the IMD 100 to indicate a desire to deactivate theelectrical signal generator 110, for example. The patient may be givenlimited control over operation of the device to an extent which may bedetermined by the program dictated or entered by the attendingphysician. The patient may also activate the IMD 100 using othersuitable techniques or apparatus.

In some embodiments, feedback stimulation systems other thanmanually-initiated stimulation may be used in the present invention. Acranial nerve stimulation system may include a sensing lead coupled atits proximal end to a header along with a stimulation lead and electrodeassemblies. A sensor may be coupled to the distal end of the sensinglead. The sensor may include a cardiac cycle sensor. The sensor may alsoinclude a nerve sensor for sensing activity on a nerve, such as acranial nerve, such as the vagus nerve 127.

In one embodiment, the sensor may sense a body parameter thatcorresponds to a symptom of a medical condition. If the sensor is to beused to detect a symptom of the medical condition, a signal analysiscircuit may be incorporated into the IMD 100 for processing andanalyzing signals from the sensor. Upon detection of the symptom of themedical condition, the processed digital signal may be supplied to amicroprocessor in the IMD 100 to trigger application of the electricalsignal to the cranial nerve, such as the vagus nerve 127. In anotherembodiment, the detection of a symptom of interest may trigger astimulation program including different stimulation parameters from apassive stimulation program. This may entail providing a higher currentstimulation signal or providing a higher ratio of on-time to off-time.

Turning now to FIG. 5 , a flowchart depiction of a method for treating amedical condition, in accordance with one illustrative embodiment of thepresent invention is provided. An electrode may be coupled to a portionof a cranial nerve to perform a stimulation function or a blockingfunction to treat a medical condition. In one embodiment, one or moreelectrodes may be positioned in electrical contact or proximate to aportion of the cranial nerve to deliver a stimulation signal to theportion of the cranial nerve (block 710). The electrodes may beoperatively coupled to at least one of main trunk of the right or leftvagus nerve, or any branch thereof. The IMD 100 may then generate acontrolled electrical signal, based upon one or more characteristicsrelating to the medical condition(s) of the patient (block 720). Thismay include a predetermined electrical signal that is preprogrammedbased upon a particular condition of a patient. The term “medicalcondition” may include epilepsy or depression, among others. Forexample, a physician may pre-program the type of stimulation to provide(e.g., conventional stimulation, microburst stimulation, or combinationconventional/microburst stimulation) in order to treat the patient basedupon the medical condition of the patient. The IMD 100 may then generatea signal, such as a controlled-current pulse signal, to affect one ormore portions of the neurological system of a patient.

The IMD 100 may then deliver the stimulation signal to the portion ofthe cranial nerve (block 730). The application of the electrical signalmay be delivered to the main trunk of the right or left vagus nerve, orany branch thereof. In one embodiment, application of the stimulationsignal may be designed to generate afferent electrical activity on thevagus nerve 127. Further, the stimulation by the IMD 100 may reduceincidents or symptoms relating to a medical condition. Application ofthe stimulation signal may be controlled so that the signal is appliedduring periods of the cardiac cycle correlated with increased afferenttraffic on the cranial nerve.

In another embodiment, application of the stimulation signal may bedesigned to promote a blocking effect relating to a signal that is beingsent from the brain, to treat the medical condition. This may beaccomplished by delivering a particular type of controlled electricalsignal, such as a controlled current signal to the cranial nerve. In yetanother embodiment, afferent fibers may also be stimulated incombination with an efferent blocking to treat a medical condition.

Additional functions, such as a detection process, may be alternativelyemployed with the embodiment of the present invention. The detectionprocess may be employed such that an external detection or an internaldetection of a bodily function may be used to adjust the operation ofthe IMD 100.

Turning now to FIG. 6 , a block diagram depiction of a method inaccordance with an alternative embodiment of the present invention isillustrated. The IMD 100 may perform a detection process, which mayinclude checking a database for physiological data, such as dataindicative of the patient's cardiac cycle (block 810). Data from thedatabase may be used for determining the timing of the delivery ofstimulation signals, e.g. timing delivery based on the patient's cardiaccycle. The detection process may encompass detecting a variety of typesof characteristics of the cardiac cycle of the patient. A more detaileddepiction of the steps for performing the detection process is providedin FIG. 7 , and accompanying description below. Upon performing thedetection process, the IMD 100 may determine whether an appropriatepoint in the cardiac cycle has been reached (block 820). Upon adetermination that an appropriate point in the cardiac cycle has notbeen reached, the detection process is continued (block 830).

Upon a determination that an appropriate time in the cardiac cycle hasbeen reached, a determination as to the type of stimulation based upondata relating to the medical condition is made (block 840). The type ofstimulation may be determined in a variety of manners, such asperforming a look-up in a look-up table that may be stored in the memory217. Alternatively, the type of stimulation may be determined by aninput from an external source, such as the external unit 270 or an inputfrom the patient. Further, determination of the type of stimulation mayalso include determining the location as to where the stimulation is tobe delivered. Accordingly, the selection of particular electrodes, whichmay be used to deliver the stimulation signal, is made.

Upon determining the type of stimulation to be delivered, the IMD 100performs the stimulation by applying the electrical signal to one ormore selected electrodes (block 850). Upon delivery of the stimulation,the IMD 100 may monitor, store, or compute the results of thestimulation (block 860). For example, based upon the calculation, adetermination may be made that adjustment(s) to the type of signal to bedelivered for stimulation, may be performed. Further, the calculationsmay reflect the need to deliver additional stimulation. Additionally,data relating to the results of stimulation may be stored in memory 217for later extraction or further analysis. Also, in one embodiment, realtime or near real time communications may be provided to communicate thestimulation result or the stimulation log to an external unit 270.

Turning now to FIG. 7 , a more detailed block diagram depiction of aparticular embodiment of the step of performing the detection process ofblock 810 in FIG. 6 , is illustrated. The system 100 may monitor one ormore signals relating to the cardiac cycle of the patient (block 910).This detection may be made by sensors residing inside the human body,which may be operatively coupled to the IMD 100. In a particularembodiment, the sensors may be located in the IMD 100. In anotherembodiment, these signals may be detected by external means and may beprovided to the IMD 100 from an external device via the communicationunit 260.

Upon acquisition of various signals, a comparison may be performedcomparing the data relating to the real-time signals or storedphysiological data to predetermined and/or stored data (block 920). Forexample, an ECG may be compared to various benchmark ECGs to determinewhether a portion of the cardiac cycle correlated with increasedafferent vagus nerve conduction has been reached. Based upon thecomparison of the collected data with theoretical, stored thresholds,the IMD 100 may determine whether an appropriate time to commence anon-time (i.e., a time to apply the electrical signal to the cranialnerve) has been reached (block 930). Based upon the determinationdescribed in FIG. 7 , the IMD 100 may continue to determine whether themedical condition is sufficiently significant to perform treatment, asdescribed in FIG. 6 .

Additionally, external devices may perform such calculation andcommunicate the results or accompanying instructions to the IMD 100. TheIMD 100 may also determine the specific cranial nerve(s), or thelocation or branch of the nerve(s), to stimulate. The IMD 100 may alsoindicate the type of treatment to be delivered. For example, anelectrical treatment alone or in combination with another type oftreatment may be provided based upon the quantifiable parameter(s) thatare detected. For example, a determination may be made that anelectrical signal by itself is to be delivered. Alternatively, basedupon a particular type of medical condition, a determination may be madethat an electrical signal, in combination with a magnetic signal, suchas transcranial magnetic stimulation (TMS) may be performed. Stimulationcan be induced by light such as from a laser.

In addition to electrical or magnetic stimulation, a determination maybe made whether to deliver a chemical, biological, or other type oftreatment(s) in combination with the electrical stimulation provided bythe IMD 100. In one example, electrical stimulation may be used toenhance the effectiveness of a chemical agent. Therefore, various drugsor other compounds may be delivered in combination with an electricalstimulation or a magnetic stimulation. Based upon the type ofstimulation to be performed, the IMD 100 delivers the stimulation totreat various medical conditions.

All of the methods and apparatuses disclosed and claimed herein may bemade and executed without undue experimentation in light of the presentdisclosure. While the methods and apparatus of this invention have beendescribed in terms of particular embodiments, it will be apparent tothose skilled in the art that variations may be applied to the methodsand apparatus and in the steps, or in the sequence of steps, of themethod described herein without departing from the concept, spirit, andscope of the invention, as defined by the appended claims. It should beespecially apparent that the principles of the invention may be appliedto selected cranial nerves other than, or in addition to, the vagusnerve to achieve particular results in treating patients havingepilepsy, depression, or other conditions.

The particular embodiments disclosed above are illustrative only as theinvention may be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown other than as describedin the claims below. It is, therefore, evident that the particularembodiments disclosed above may be altered or modified and all suchvariations are considered within the scope and spirit of the invention.Accordingly, the protection sought herein is as set forth in the claimsbelow.

What is claimed:
 1. A method of treating a medical condition in apatient comprising: detecting a portion of a cardiac cycle of thepatient; detecting a portion of a respiratory cycle of the patient basedon using a high frequency component of a heart rate variability powerspectrum to determine when inspiration occurs; applying to a vagus nerveof the patient, in response to the detecting of the portion of thecardiac cycle and the inspiration occurrence, a pulsed electrical signalcomprising a plurality of microbursts where the pulsed electrical signalis applied during inspiration, wherein each microburst is characterizedby: from 2 to 20 pulses per microburst; an interpulse interval betweenadjacent pulses of the microburst is about 1 to about 20 milliseconds;and a microburst duration of less than 1 second; and wherein eachmicroburst is separated from an adjacent microburst by an interburstperiod of at least 100 milliseconds.
 2. The method of claim 1, whereinthe detecting a portion of the cardiac cycle of the patient comprisesdetermining a heart rate variability (HRV) parameter, and whereinapplying the pulsed electrical signal to the vagus nerve comprisesapplying the pulsed electrical signal to the vagus nerve in response tothe determined HRV parameter.
 3. The method of claim 2, furthercomprising increasing the heart rate variability parameter of thepatient by applying the pulsed electrical signal to the vagus nerve. 4.The method of claim 1, wherein the detecting a portion of the cardiaccycle of the patient comprises determining an inhibition phase of thecardiac cycle and the applying further comprises not applying the pulsedelectrical signal during the inhibition phase of the cardiac cycle. 5.The method of claim 4, wherein applying the pulsed electrical signalcomprises applying the pulsed electrical signal after a delay periodfollowing detection of an R-wave of the cardiac cycle of the patient,and not applying the pulsed electrical signal for a period of from aremaining portion of the same cardiac cycle to one or more subsequentcardiac cycles.
 6. The method of claim 1, wherein the detecting aportion of the cardiac cycle of the patient comprises detecting at leasta portion of the cardiac cycle selected from a group consisting of a Pwave, an R wave, an R-R interval, a QRS complex, a T wave, and an entirePQRST cycle.
 7. The method of claim 1, further comprising sensing atemperature of the patient and wherein applying comprises applying thepulsed electrical signal in response to the temperature of the patient.8. The method of claim 1, further comprising applying a second pulsedelectrical signal to the vagus nerve without reference to the cardiaccycle of the patient.
 9. The method of claim 8, wherein the secondpulsed electrical signal is not a microburst signal.
 10. The method ofclaim 1, wherein applying the pulsed electrical signal comprisesapplying the pulsed electrical signal after a delay period followingdetection of a beginning of inspiration, and not applying the pulsedelectrical signal for a period from a remaining portion of the samerespiratory cycle to one or more subsequent respiratory cycles.
 11. Asystem for treating a medical condition in a patient comprising: asensor configured for sensing at least a portion of a cardiac cycle ofthe patient and a respiratory cycle of the patient; a lead assemblycomprising at least one electrode configured for being coupled to avagus nerve of the patient; an implantable medical device coupled to thelead assembly and the sensor and comprising: a detection unit coupled tothe sensor configured for detecting the portion of the cardiac cycle ofthe patient and an inspiration phase of the respiratory cycle of thepatient; a stimulation unit capable of generating and delivering apulsed electrical signal comprising a plurality of microbursts to the atleast one electrode in response to the detection unit detecting theportion of the cardiac cycle and the inspiration phase of therespiratory cycle of the patient, wherein each microburst ischaracterized by: from 2 to 20 pulses per microburst; an interpulseinterval between adjacent pulses of the microburst is about 1 to about20 milliseconds; and a microburst duration of less than 1 second; andwherein each microburst is separated from an adjacent microburst by aninterburst period of at least 100 milliseconds; and a controllerconfigured for controlling the implantable medical device to apply thepulsed electrical signal comprising the plurality of microbursts to thevagus nerve of the patient during the inspiration phase using the atleast one electrode.
 12. The system of claim 11, wherein the detectionunit is further configured to determine a heart rate variability (HRV)parameter, and wherein the stimulation unit is further configured forgenerating and delivering the pulsed electrical signal to the vagusnerve in response to the determined HRV parameter.
 13. The system ofclaim 11, wherein the detection unit is further configured to utilize ahigh frequency component of a HRV power spectrum to determine wheninspiration occurs.